Studies suggest that an inflammatory response around intracerebral hemorrhage (ICH) contributes to the pathophysiology. The use of bacterial collagenase (BC), which proteolytically degrades the blood-brain barrier, results in the coalescing of multifocal hemorrhages into a hematoma that models hemorrhagic transformation (HT). Blood products initiate an inflammatory response with endogenous proteolysis, edema formation, and apoptotic and necrotic cell death. Tissue inhibitor of metalloproteinases-3 (TIMP-3) facilitates apoptosis in neurons through the external pathway involving Fas/Fas ligand. Studies by the Sponsor and collaborators have shown that TIMP-3 null mice have fewer apoptotic neurons after an ischemic insult. Here, we propose that the gelatinases and TIMP-3 play a role in exacerbating striatal damage following BC-induced ICH. We plan to initially characterize the proteolytic events and cell death mechanisms that occur in the mouse model of ICH, and to examine the role of TIMP-3 in facilitating apoptosis, or whether apoptosis occurs through the intrinsic pathway in this model. Understanding the cascade of events in HT will ultimately allow for therapeutic intervention by the preservation of neurons in the hematomal areas at risk of undergoing apoptosis, and thus present a window of opportunity for intervention in this delayed cell death. [unreadable] [unreadable]